1. Field of the Invention
This invention relates to antineoplastic agents and in particular to the encapsulation of such agents in liposomes.
2. Description of the Prior Art
As has been established by various investigators, cancer therapy employing antineoplastic agents can in many cases be significantly improved by encapsulating the antineoplastic agent in liposomes, rather than administrating the agent directly into the body. See, for example, Forssen, et. al., (1983), Cancer Res., 43:546; Gabizon, et. al., (1982), Cancer Res., 42:4734; and Olson, et. al., (1982), Eur. J. Cancer Clin. Oncol., 18:167; but see Abra, et. al., (1983), Cancer Chemother. Pharmacol., 11:98. Incorporation of such agents in liposomes changes their antitumor activities, clearance rates, tissue distributions, and toxicities compared to direct administration. See, for example, Rahman, et. al., (1982), Cancer Res., 42:1817: Rosa, et. al., (1982) in Transport in Biomembranes: Model Systems and Reconstitution, R. Antolini et. al., ed., Raven Press, New York. 243-256; Rosa, et. al., (1983), Pharmacology, 26:221; Forssen, et. al., supra; Gabizon, et. al., supra; and Olson, et. al., supra. For example, it is well known that the cardiotoxicity of the anthracycline antibiotics daunorubicin and doxorubicin (adriamycin) and their pharmaceutically acceptable derivatives and salts can be significantly reduced through liposome encapsulation. See, for example, Forssen, et. al., supra; Olson, et. al., supra; and Rahman, et. al., supra. Also, incorporation of highly toxic antineoplastic agents in liposomes can reduce the risk of exposure to such agents by persons involved in their administration.
The use of liposomes to administer antineoplastic agents has raised problems with regard to both drug encapsulation and drug release during therapy. With regard to encapsulation, there has been a continuing need to increase trapping efficiencies so as to minimize the lipid load presented to the patient during therapy. In addition, high trapping efficiencies mean that only a small amount of drug is lost during the encapsulation process, an important advantage when dealing with the expensive drugs currently being used in cancer therapy.
As to drug release, many antineoplastic agents, such as adriamycin, have been found to be rapidly released from liposomes after encapsulation. Such rapid release diminishes the beneficial effects of liposome encapsulation and thus, in general, is undesirable. Accordingly, there have been continuing efforts by workers in the art to find ways to reduce the rate of release of antineoplastic agents and other drugs from liposomes.
In addition to these problems with encapsulation and release, there is the overriding problem of finding a commercially acceptable way of providing liposomes containing antineoplastic agents to the clinician. Although the production and loading of liposomes on an "as needed" basis is an acceptable procedure in an experimental setting, it is, in general, unsatisfactory in a clinical setting. Accordingly, there is a significant and continuing need for methods whereby liposomes, with or without encapsulated drugs, can be shipped, stored and in general moved through conventional commercial distribution channels without substantial damage.